Method and composition for administering an NMDA receptor antagonist to a subject

Abstract

The invention provides methods and compositions for administering an NMDA receptor antagonist (e.g., memantine) to a subject.

1. A solid pharmaceutical composition in a unit dosage form for once daily oral administration comprising an extended release formulation of 5 to 40 mg memantine or pharmaceutically acceptable salt thereof, wherein administration of a dose of the composition to a human subject provides a plasma memantine concentration profile, as measured in a single-dose human PK study, characterized by a change in memantine concentration as a function of time (dC/dT) that is less than 50% that of an immediate release dosage form comprising the same dose of memantine as the composition, wherein the dC/dT is measured between the time period of 0 to Tmax of the immediate release form of memantine. 
     
     
       2. The composition of  claim 1  wherein the concentration profile is further characterized by a memantine Tmax of at least 19 hours. 
     
     
       3. The composition of  claim 1  or  2  wherein the concentration profile is further characterized by a maximum memantine plasma concentration to mean memantine plasma concentration ratio (Cmax/Cmean) of about 2.5 to 2 at 1 hour to at least 6 hours after administration. 
     
     
       4. The composition of  claim 3  wherein the Cmax/Cmean is about 2.5 to 2 at 1 hour to at least 9 hours after administration. 
     
     
       5. The composition of  claim 1 , wherein at least 98% of the memantine or pharmaceutically acceptable salt thereof is in an extended release form. 
     
     
       6. The composition of  claim 1 , wherein the unit dosage form is a capsule and wherein the memantine or pharmaceutically acceptable salt thereof is formulated as pellets. 
     
     
       7. The composition of  claim 6 , wherein the pellets comprise an extended release coating. 
     
     
       8. The composition of  claim 7 , wherein the extended release coating comprises an insoluble matrix polymer and a water soluble material. 
     
     
       9. The composition of  claim 8 , wherein the insoluble matrix polymer comprises ethyl cellulose and the water soluble material comprises polyvinylpyrrolidone. 
     
     
       10. The composition of  claim 1  comprising 12.5-40 mg memantine or pharmaceutically acceptable salt thereof. 
     
     
       11. The composition of  claim 1  comprising 25-40 mg memantine or pharmaceutically acceptable salt thereof. 
     
     
       12. The composition of  claim 1  having a memantine in vitro dissolution profile ranging between 0.1-20% in one hour, 5-30% in two hours, 40-80% in six hours, and 50-90% in 10 hours, wherein the dissolution profile is determined using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±0.5° C., in 500 ml water. 
     
     
       13. The composition of  claim 12  in which the dissolution profile is at least 70% in 10 hours and at least 90% in 12 hours. 
     
     
       14. The composition of  claim 1  having a memantine in vitro dissolution profile ranging between 0.1-20% in one hour, 5-30% in two hours, 40-80% in six hours, and 50-90% in 10 hours, wherein the dissolution profile is determined using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±0.5° C., in an acidic dissolution medium. 
     
     
       15. The composition of  claim 1 , wherein the extended release formulation of memantine or pharmaceutically acceptable salt thereof comprises ethyl cellulose, polyethylene glycol, hydroxypropylmethyl cellulose and polyvinylpyrrolidone.